Dramatic increases in the incidence of esophageal adenocarcinoma (EA), a rapidly lethal cancer, have occurred in the U.S. and Western Europe over the last two decades. The vast majority of cases occur among Caucasian men. The underlying reasons for the rapid increase in incidence and the unusual gender and race patterns remain largely unknown, although the increasing prevalence of obesity in the U.S. likely plays a role. Most EAs arise in a metaplastic epithelium termed Barrett's esophagus (BE) that develops in approximately 10 percent of persons who have chronic gastroesophageal reflux. Persons with BE are at high risk, with approximately 0.5 - 1.0 percent per year progressing to cancer. Environmental exposures and host factors may be important determinants of the likelihood of developing genetic instability in BE, and of progressing through a succession of abnormalities to cancer. In this well-established cohort (N=461; mean follow-up = 5 years), suspected risk and protective factors for EA will be examined to quantify the extent to which they predict risk of neoplastic progression in persons with BE, and to identify particular genetic and histologic abnormalities with which they are most closely associated. In addition to EA as an outcome, intermediate endpoints will be used that have been validated, or are expected to be as part of Projects 1 and 3, as predictors of EA. These include aneuploidy, elevated 4N fraction, high grade dysplasia, and alterations (LOH, mutation, methylation) involving p53 and p16. Specific aims are to evaluate as potential protective factors: a) use of non-steroidal anti-inflammatory drugs (NSAIDs), and b) increased serum selenium concentration; and to evaluate as factors that may increase risk: c) overweight and an abdominal fat distribution, d) bile reflux, and e) a diet high in fat and low in fruits and vegetables. Proportional hazards regression will be the main analytic approach. Successful attainment of the above specific aims will likely lay the scientific foundation for future prevention trials by identifying important risk factors for esophageal adenocarcinoma, identifying specific interventions that could be tailored to individual patients, and illuminating mechanisms of action which could be tested experimentally.